Microglial TREM2 Overexpression Ameliorates Cognitive Deficits in Alcoholic Dementia via the Syk/PI3K/GSK-3β Pathway

摘要

Objective:Alcohol Use Disorder (AUD) is a significant risk factor for dementia and a major public health issue worldwide.Long-term alcohol consumption can induce alcoholic dementia (AlD) through neurotoxicity,structural damage to the brain and blood-brain barrier,and inflammation-mediated neuronal injury,leading to cognitive impairment.Microglia,the resident immune cells of the central nervous system,play crucial roles in neuroinflammation,synaptic pruning,and neural repair.Triggering receptor expressed on myeloid cells 2 (TREM2),an innate immune receptor highly expressed in microglia,helps shape microglial activation.This study aims to elucidate the role and mechanism of TREM2 in alcoholic dementia.Methods:3×Tg AD and control mice were randomly divided into a water group and a two-bottle free-choice group(25%ethanol) for 16 weeks to establish an AlD model.TREM2 was overexpressed in the mouse hippocampus via stereotactic injection.Cognitive function was assessed using the Morris water maze,Y-maze,and novel object recognition tests.Microglial morphology and Aβ plaques were observed via transmission electron microscopy.Brain pathology was evaluated using silver staining and Nissl staining.Protein and gene expression of TREM2 pathway components were detected using immunohistochemistry,immunofluorescence,Western blot,and RT-qPCR.Results:TREM2-overexpressing 3×Tg-AD mice exhibited enhanced learning and memory capabilities.In the Morris water maze test,they showed shorter escape latency and more efficient swimming paths during the navigation phase,and spent more time in the target quadrant with increased platform crossings duringthe probe phase.The Y-maze test revealed a higher rate of novel arm entries,and the novel object recognition test indicated a significantly increased recognition index and more exploratory behavior.TREM2 upregulation reduced Aβ plaque deposition,attenuated Tau hyperphosphorylation,and increased neurotrophic factors such as BDNF,supporting synaptic plasticity.Western blot analysis showed upregulated expression of DAP12,p-Syk,and p-PI3K,along with inhibited activity of GSK-3β.Conclusion:TREM2 overexpression improves cognitive function and exerts neuroprotective effects in a mouse model of alcoholic dementia,primarily through activation of the Syk/PI3K/GSK-3β pathway.TREM2 enhances microglial clearance of Aβ and reduces Tau hyperphosphorylation,ameliorating cognitive deficits.These findings highlight TREM2 as a potential therapeutic target for alcoholic dementia.

关键词

alcoholic dementia / TREM2 / microglia / Aβ clearance / tau phosphorylation / cognitive impairment